Use of angiotensin receptor blockers (ARBs) may not be associated with an increased risk of MI after all, a meta-analysis showed.

Action Points

Explain that use of angiotensin receptor blockers may not be associated with an increased risk of MI after all, according to a meta-analysis.

Note that the analysis also found that ARBs were associated with a reduction in the risk of stroke, heart failure, and new-onset diabetes.

Us﻿e of angiotensin receptor blockers (ARBs) may not be associated with an increased risk of MI after all, a meta-analysis showed.

In a pooled analysis of 37 randomized trials that included 147,020 patients, ARB use compared with placebo or active control was not associated with MI risk (RR 0.99, 95% CI 0.92 to 1.07), Sripal Bangalore, MD, of NYU Langone Medical Center, and colleagues reported online in BMJ.

Ever since the VALUE trial -- which compared valsartan (Diovan) with amlodipine for reducing cardiac morbidity and mortality -- demonstrated that there was a 19% relative increase in the risk of MI in the valsartan arm, the safety of ARBs has been debated.

The findings of this meta-analysis, however, argue against any clinically meaningful increase in MI risk -- which was a secondary endpoint in the VALUE trial, according to Bangalore.

"Our analysis is the largest meta-analysis to date on this subject," he told MedPage Today.

"Based on the data, we can have adequate power to rule out even a 0.3% absolute increase in the risk of [MI] with ARBs," he wrote in an email. "The analysis assures physicians and patients that ARBs as a class are safe."

Bangalore and his colleagues excluded trials in which ARBs were used with ACE inhibitors or were not used as first-line therapies. For the 37 included studies, there were 39 comparator arms -- 17 with placebo and 22 with active treatment.

Through an average follow-up of 3.3 years, ARBs were not associated with increased risks of MI, death, cardiovascular death, or an﻿gina pectoris compared with either placebo or active treatment control (P>0.05 for all).

The researchers used a statistical technique called trial sequential analysis to verify the findings.

"While traditional meta-analysis does not take into consideration the sample size, the accrued number of events, or the power, a trial sequential analysis does," Bangalore said.

Using this method, the researchers ruled out even a 5% to 7.5% relative increase (or a 0.3% absolute increase) in MI risk.

"The analyses, however, do not rule out a [less than] 0.3% absolute increase of myocardial infarction with angiotensin receptor blockers, though this is likely to be clinically less important," they wrote.

They noted in their paper that the reason VALUE demonstrated an increase in MI risk in the ARB arm of the trial was unclear.

"In VALUE, those in the amlodipine arm had a modest but significantly lower blood pressure than those in the angiotensin receptor blockers arm (1.8 mm Hg systolic and 1.5 mm Hg diastolic) and a significantly lower blood pressure in the first three months, but whether this difference can explain the results has been contested," Bangalore and his colleagues wrote.

They added that randomized trials published since VALUE -- including ONTARGET and TRANSCEND -- have not found an increase in adverse outcomes in the ARB arms, although none were powered for individual outcomes.

In the current study, trial sequential analysis also identified "firm evidence," according to the researchers, of at least a 1% relative decrease in stroke risk (compared with placebo only), at least a 5% relative decrease in heart failure risk, and at least a 4% relative decrease in new-onset diabetes risk.

The authors acknowledged some limitations of the meta-analysis, including the inability to adjust for drug doses or compliance with assigned treatments, the possibility of confounding by unmeasured factors, and the fact that not all of the trials reported each of the outcomes analyzed.

Bangalore reported that he had no conflicts of interest. One of his co-authors has been an occasional consultant or speaker for Novartis, Daiichi Sankyo, Sanofi, and Savient Pharmaceuticals, and has received grants from Novartis, Forest, and Boehringer Ingelheim.

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